1. Field of the Invention
The present invention relates to an aldose reductase inhibitor represented by the formula (I): ##STR3## wherein R.sub.1 is (CH.sub.2).sub.2 COOH and R.sub.2 is phenyl or p-hydroxyphenyl, or R.sub.1 and R.sub.2 are combined together to form a group of the formula: ##STR4## The present invention also relates to a microorganism producing said inhibitor and to a process for producing said inhibitor.
2. Related Art
The incidence rate of diabetes has hitherto increased and various complications thereof have become a quite serious problem. The diabetic complications may be caused by, for example, accumulation of polyol (e.g., sorbitol), free radical peroxidation, and glucosylation of proteins at the site of lysine residues. An inhibitor for aldose reductase (abbreviated hereinafter as AR) relating to polyol metabolism is expected to serve as a medicine for diabetic complications, that is, diseases arising from diabetes such as diabetic neuropathy, diabetic cataract, diabetic keratopathy, diabetic retinopathy, and diabetic nephropathy. So there have been many investigations into the development of such a medicine. Tolrestat represented by the following formula (II) (SimardDuquesne, N. et al., Metabolism 34, 885-892, 1985) and WF-3681 represented by the following formula (III) (JP Kokoku No. 3-52458) are known as AR inhibitor. But AR inhibitor structurally similar to the compound of this invention is not known at all. ##STR5##
It has been revealed that AR as a rate-limiting enzyme in the metabolic pathway of polyol is present in blood vessels, peripheral nerves, lenses, retinae, and so forth, in which many diabetic complications often occur. Therefore, the significance of AR became understood in relation to diabetes. In the state of glycophilia such as diabetes, a larger amount of glucose than that of glucose capable of being metabolized in the glycolysis system is present in cells and the metabolism of glucose in the metabolic pathway of a polyol can readily be promoted because glucose is used as a substrate for AR. As a result, the abnormal accumulation of sorbitol is further enhanced. Sorbitol is a relatively stable substance; once the cells produce sorbitol, very little extracellular release of the sorbitol is found. The unbalance between the production and metabolism causes the intracellular accumulation of this sugar alcohol. This results in hypertonicity and osmotic uptake of water, thereby making it impossible to maintain the normal function of the cells and exhibiting a disorder of the cells. If the AR activity is inhibited, the abnormal intracellular accumulation of sorbitol can be avoided and the normal function of the cells can be maintained. Accordingly, the present inventors have made an effort to search compounds having an AR-inhibiting activity.